Brain uptake of morphine was shown to be elevated in rats by alkalosis, due to increased plasma concentrations of uncharged morphine and penetration at the blood brain barrier. Melphalan, an anticancer alkylating agent, could be measured in the blood of animals and its pharmakinetics determined. It was shown to enter the brain of rats via an amino acid transport system at the blood-brain barrier; its entry also was related to plasma protein binding. Glucose transport into the brain was characterized by multicompartmental model involving capillary profiles of glucose. The blood-brain barrier was not affected by dimethylsulfoxide, but could be opened in rats by intracarotid infusion of a hypertonic arabinose solution. The rate of reclosure was related to the size of intravascular tracer, indicating that tight junctions between cerebrovascular endothelial cells were modified. Positron emission tomography in monkeys, using [Ga68] EDTA, was used to examine barrier function. The rate of loss of methotrexate from the brain, following loading in association with osmotic barrier opening, indicated intracellular uptake. Chemical modification of water-soluble drugs was used to enhance drug entry into the brain.